Sequential administration of partitioned absorption aspirin or active aspirin derivative and cox-2 inhibitor

ABSTRACT

Described herein are an aspirin or active aspirin derivative and a COX-2 inhibitor, at least one of which has an enteric or partial enteric coating, administered in combination yet delivered sequentially, for the treatment and prophylactic treatment of diseases, symptoms and conditions. In some embodiments, the COX-2 inhibitor has the enteric coating; however, the aspirin or active aspirin derivative may additionally or alternately have the enteric coating. In all embodiments, the drug having the enteric coating or enteric formulation is targeted for absorption in the small intestine or colon, or both the small intestine and the colon.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/571,781, filed Dec. 16, 2014, which claims the benefit of U.S.Provisional Application No. 61/916,986, filed Dec. 17, 2013, the entiredisclosures of which are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to prophylactic or targeted prophylactictreatment of diseases and conditions, as well as compositions forprophylactic or targeted treatment of diseases and conditions.

Examples of diseases and conditions that can be treated by short-termadministration include acute pain, fever, dysmenorrhea, acute migraine,prevention of migraine in a time window, and prevention ofintra-abdominal adhesions. Examples of diseases and conditions that canbe treated by long-term administration include osteoarthritis, otherarthritides, subacute and chronic pain, prophylaxis of subacute orchronic migraine, cancer prevention, cancer treatment, and prevention ortreatment of pre-cancerous intestinal (colon or rectal) polyps, andfamilial adenomatous polyposis (FAP).

BACKGROUND

It is advantageous to have a drug formulation that can deliver twodifferent compounds separated by a significant period of time. A drugformulation comprising aspirin and an NSAID (non-steroidalanti-inflammatory drug) may be delivered separated by a significantperiod of time. Alone, aspirin appears to be rapidly absorbed in thestomach and the small intestine and also in the colon. Alone, COX-2inhibitors have poor solubility in humans, and therefore cause a slowabsorption in the small intestine (Chourasis & Jain, J. Pharm. Sci.,Vol. 6, p. 33-36). It would be advantageous to combine a COX-2 inhibitorand an aspirin derivative to deliver the COX-2 inhibitor in a form thatencourages rapid absorption and the aspirin or aspirin activederivative's release is delayed.

COX-2 inhibitors are predominantly BCS Class II molecules, meaning thebioavailability of the compound is limited by their solvation rate.Recently, COX-2 inhibitors have been formulated in ways to enhancesolubility and increase the rate of absorption. One way to enhancesolubility relies on COX-2 inhibitors high lipophilicity and uses lipidbased systems to administer the compound (Homar et. al., J. Microencaps,Vol. 29, p. 479-484; Thakkar et. al., AAPS Pharm. Sci. Tech., Vol. 6,Art. 12, p. E65-E73). Another approach is to add bile salts to the COX-2inhibitor (Morgen et. al., Pharm. Res. Vol. 29, p. 427-440). Theaddition of bile salts provides a significant increase in thedissolution rate and a commensurate increase in the rate of absorption.Yet another approach is to use COX-2 inhibitor conjugates (Al-Hilal et.al., Adv. Drug Delivery Rev. Vol. 65, p 845-864).

A more useful approach to increase solubility has been determined. Thesolubility characteristics of spray dried amorphous dispersions of drugsare enhanced (Fini et. al., Eur. J. Pharm. & Biopharm., Vol. 70, p409-420; Dhumal et. al., Acta. Pharmaceutica, Vol. 57, p. 287-300).Celeboxib (the commercial name of a COX-2 inhibitor) and a combinationof PVP (alpha-Pyrrolidinopentiophenone) and Carageenan suggest asynergistic action of two polymers to stabilize the material aftercompaction (Dhumal). The use of spray dried dispersions of poorlysoluble drugs to improve solubility and shorter T_(max) and higherC_(max) values of the crystalline form of the drug is well known. Spraydried dispersions have a limited cost and limited regulatory issues.

In some embodiments, a delayed release of drugs is desired, while inother embodiments, a several hour delay between immediate release ofdrugs is desired. Other embodiments desire to slow the release of drugsfrom a dosage form. These technologies provide a steady release of adrug along the gastrointestinal tract in order to minimize the drug'sC_(max) (see i.e., Shahzad et. al., Adv. Clin. Expt. Med., Vol. 22, p177-183; Gaucher et. al. Eur. J. Pharmaceutics & Biopharm., Vol. 76, p.147-158; Bejugam et. al., J. of Microencapsulation, Vol. 25, p. 577-583;Dea-Ayuela et. al., Drug Targeting, Vol. 14, p. 567-575). A steadyrelease also reduces the probability of side effects and extends theblood levels of the drug.

In contrast, it may be more advantageous to provide a “burst” release ofthe drug (Alvarez-Fuentes et. al., J. Drug Targeting, Vol. 12, p.607-612; Cole et. al., Int. J. Pharmaceutics, Vol. 231, p. 83-95). Forexample, an immediate release of a COX-2 inhibitor at a specific timeafter dosing may be desired.

A system used to provide a timed release of a drug utilizes an entericcoated matrix (Alvarez-Fuentes). This also slowed the subsequent releaseof the drug, which can be affected by the presence of other inertmaterials. HPMC capsules (hydroxypropyl methylcellulose) may also beenteric coated (Cole). The in-vivo gamma scintigraphy data shows thatenteric coated HPMC capsules may provide a controlled delivery.Potential enteric coatings may be Eudragit® or Caps Canada, whichenables the drug to be absorbed in specific areas of the intestine. Anadditional layer of immediate release drug prepared as a spray drieddispersion (for rapid dissolution) would provide a biphasic release.

The process of combining an immediate and delayed release mechanism intoone simple biphasic release product is advantageous (Maram et. al., Int.J. Pharm. Sci., Vol. 13, p. 116-120). For example, a complex,compression coated formulation of Tramado was mimicked using a spraycoating process (Maram). No matter how the drug is coated, the entericcoating must be a high quality (Zaid & Qaddomi, Pakistan J. ofPharmaceutica, Vol. 25, p. 59-64; Felton & Porter, Expert Opin. On DrugDelivery, Vol. 10, p. 421-435). An adaptation of the Maram approachwould be to replace the compression coating with a spray coatednanoparticulate COX-2 inhibitor such as celecoxib or celecoxib analogue.

SUMMARY OF THE INVENTION

One particular embodiment of this disclosure is a method of sequentiallyadministering an aspirin or active aspirin derivative and a COX-2inhibitor for partitioned absorption, at least one of which has anenteric or partial enteric coating for bioabsorption in a patient'ssmall intestine or colon.

In one embodiment, the present invention provides a method forsequentially administering an aspirin or active aspirin derivative and aCOX-2 inhibitor for partitioned absorption, at least one of which has anenteric or partial enteric coating for bioabsorption in a patient'ssmall intestine or colon. The COX-2 inhibitor and the aspirin or theaspirin derivative may have an enteric or partial enteric coating. Themethod may be for the treatment of diseases and conditions wherebioabsorption in the small intestine is desired or where bioabsorptionin the colon is desired. The administration of the aspirin or activeaspirin derivatives and the COX-2 inhibitor may be long-term,short-term, or may be periodic.

In another embodiment, the present invention provides a method for thetreatment of diseases and conditions such as osteoarthritis, otherarthritides, subacute and chronic pain, prophylaxis of subacute orchronic migraines, cancer prevention, cancer treatment, and preventionor treatment of pre-cancerous intestinal (colon or rectal) polyps, andfamilial adenomatous polyposis (FAP). The method may also be for thetreatment of diseases and conditions including dysmenorrhea, preventionof dysmenorrhea, menstrual or pen-menstrual migraines, prevention ofmenstrual or peri-menstrual migraines, prevention or treatment ofdysmenorrhea and menstrual or pen-menstrual migraines in patients withboth conditions, and prevention or treatment of migraines in a patientwith recurring time windows where there is a need to be free of migrainesymptoms during the time windows. The method may also be for thetreatment of diseases and conditions including acute pain, fever,dysmenorrhea, acute migraine, prevention of migraine in a time window,or prevention of intro-abdominal adhesions.

The aspirin or active derivative of aspirin of the present method maycomprise at least one of ASA, PC-ASA, PL2200, PA8140, and PA32540. TheCOX-2 inhibitor of the method may comprise celecoxib, celecoxibanalogue, PC-celecoxib, or a PC-celecoxib analogue.

In yet another embodiment, the method includes providing a coating thatis pH-sensitive, time-sensitive, and/or microflora-activated.

In still yet another embodiment, a kit comprising an aspirin or activeaspirin derivative and a COX-2 inhibitor, at least one of which has anenteric or partial enteric coating is provided. The COX-2 inhibitor mayhave an enteric or partial enteric coating. The aspirin or activeaspirin derivative may have an enteric or partial enteric coating.

Another particular embodiment of this disclosure is a kit comprising anaspirin or active aspirin derivative and a COX-2 inhibitor, at least oneof which has an enteric or partial enteric coating.

Yet another embodiment of this disclosure is an empty or partially emptykit. The kit may contain the ASA or active derivation, allowing a userto add the COX-2 inhibitor, or the kit may contain the COX-2 inhibitor,allowing a user to add the ASA or active derivation. The COX-2 inhibitormay have an enteric or partial enteric coating or a time-sensitivecoating. The aspirin or active aspirin derivative may have an enteric orpartial enteric coating or a time-sensitive coating.

These and various other features and advantages will be apparent from areading of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present embodiments are directed to use of, in combination yetdelivered sequentially, an aspirin or active aspirin derivative and aCOX-2 inhibitor, at least one of which has an enteric or partial entericcoating. The aspirin component may be a combination of two or moreaspirin or active aspirin derivatives, at equal or unequal portions. Theaspirin or active aspirin derivative and a COX-2 inhibitor combinationis used for treatment and prophylactic treatment of diseases, symptomsand conditions where partial or complete bioabsorption in the smallintestine or colon of at least one component is desired in order toreduce GI side effects. In some embodiments, the COX-2 inhibitor has theenteric coating. In alternative embodiments, the aspirin or activeaspirin derivative has the enteric coating for embodiments where smallintestinal or colonic targeting is desired. In all embodiments, anenteric coating or enteric formulation means the drug release istargeted for absorption in the small intestine or colon, or both thesmall intestine and the colon, rather than in the stomach.

The drug combination, when administered in combination yet deliveredsequentially or at offsetting time periods, is particularly suited fortreating chronic inflammation that interferes with function (and that isgenerally targeted by COX-2 inhibitors) in the moveable bony joints,cartilage, and proximate soft tissue areas. The drug combination is alsosuited for other conditions such as migraine, dysmenorrhea, preventionof pre-cancerous polyps with or without familial adenomatous polyposis(FAP), prevention of cancer, treatment of cancer, and prevention ofpost-surgical adhesions, in which the target tissue is generally thoughtto be in a soft tissue location other than moveable bony joints,cartilage, and proximate soft tissue areas. For example, with respect tomigraine a possible target tissue is the peri-vascular tissue on thesurface of the brain that is close to the skull but not close to movingjoints. Inflammation or neuro-transmitter modulation within the brain isanother possible target of the drug combination for migraine treatment(or other brain disorders such as mood disorders or schizophrenia).

In all embodiments, the aspirin or active derivative of aspirin (forexample phosphatidylcholine treated aspirin or PC-ASA, PL2200 availablePLX Pharma Inc, Houston, TX, or PA8140 and PA32540 both available fromPozen Inc, Chapel Hill, NC) has an anti-platelet effect whether theformulation is non-enteric, enteric, or partially enteric. The COX-2inhibitor, such as celecoxib, celecoxib analogue, phosphatidylcholinetreated celecoxib or PC-celecoxib, or phosphatidylcholine treatedcelecoxib analogue or PC-celecoxib analogue, does not have ananti-platelet effect whether the formulation is non-enteric, enteric orpartially enteric.

The use of NSAID drugs has been limited due to the resulting GI sideeffects (exemplified by aspirin and conventional NSAIDs) and increasedcardiovascular risk, which is greater in COX-2 inhibitors but alsopresent when conventional NSAIDS are used. It is not known whether theoverall cardiovascular risk associated with NSAIDs would be reduced moreif aspirin were to be combined with a COX-2 inhibitor as opposed to aconventional NSAID. Conventional NSAIDs, including aspirin, are known tocause GI side effects and intolerance. An adverse drug interaction hasbeen identified when aspirin and other NSAIDs, including COX-2inhibitors, are taken together. This adverse interaction may lead to GIerosions, ulceration, and slower healing of existing GI lesions.

Experts have stated that COX-2 inhibitors should not be used in certainconditions, such as the prevention of migraines or migraines, because ofan increased cardiovascular risk. The use of celecoxib with aspirin (oractive aspirin derivative) for prophylactic treatment of migraines isreported in US Pub No 2003/0212050, the complete disclosure of which isincorporated herein by reference. Others have since proposed combiningCOX-2 inhibitors with aspirin and/or antioxidant flavonoids.

Lichtenberger, in Drugs of Today 2009, 45 (12):877-890, has proposedreducing the GI risk of NSAIDS, including PL2200 which is an activeaspirin derivative available from PLX Pharma Inc., by associating theNSAID in a non-covalent bond with a component of soy lecithin(phosphatidylcholine or PC). Lichtenberger proposed a potential clinicaluse of this phosphatidylcholine coating or PLX technology when a COX-2inhibitor is prescribed concurrently with aspirin or conventional NSAID.In particular, Lichtenberger stated the PLX active derivative of aspirin(i.e., PC-ASA) may be useful when combined with celecoxib in the settingof a chronic inflammatory disease in patients with known cardiacdisease. PC-ASA, when combined with celecoxib, resulted in less rodentGI toxicity than aspirin alone or a combination of celecoxib and ASA.However, this paper also showed the combination reduced, but did noteliminate rodent GI toxicity, when celecoxib and PC-ASA were usedtogether.

In his paper cited above, Lichtenberger refers to “high-risk individualssuffering from chronic inflammatory and cardiac diseases” suggesting a“potential therapeutic role for PC-associated aspirin and perhaps otherPC-NSAIDs” in “both the prevention of mucosal injury and treatment ofpre-existing ulcers” “when patients are placed on regimens that requirethe concomitant use of both a coxib and a conventional NSAID.”Lichtenberger also twice refers to a choice other than aspirin or activeaspirin derivative: the first time he seems to suggest that a PC-NSAIDthat is not a derivative of aspirin (and likely not a COX-2 inhibitor)might be useful; and the second time he uses the term “conventionalNSAID” which may include many other choices besides aspirin (forexample, a PC-NSAID which may or may not have any cardio-protectiveeffect). Overall, Lichtenberger suggests that while providers maycurrently be forced to use this risky combination for this patientgroup, in the future providers may consider switching from aspirin toPC-ASA when the patient has cardiac disease and requires a long-termCOX-2 inhibitor treatment; alternatively, providers can look at one (ormore) of the other PC-NSAID products.

Unlike Lichtenberger's findings, the combination of aspirin or activeaspirin derivative and COX-2 inhibitors, according to the presentinvention, further reduces GI side effects, symptoms and/or toxicity inpart by targeting separate areas of the GI tract (for partitionedabsorption) when the use of this combination is needed or indicated andalso by using separate time windows when needed or indicated. This isaccomplished by the present invention by including an enteric coating onat least one of the aspirin or active aspirin derivative and COX-2inhibitor in order to target bioabsorption, for example, to the colonand small intestine.

There are studies indicating that COX-2 inhibitors have increasedcardiovascular risk to a greater extent than traditional NSAIDs evenwhen used for short periods of time. This consideration is even moreimportant if the condition being treated presents an increasedcardiovascular risk (e.g., migraine, rheumatoid arthritis).

A need exists for the combination of COX-2 inhibitors (e.g., celecoxib,celecoxib analogue, PC-celecoxib, or PC-celecoxib analogue) and aspirinor active aspirin derivatives (e.g., PC-ASA and PL2200) for short-termuse for the following conditions: acute pain, fever, dysmenorrhea, acutemigraine, prevention of migraine in a time window, and prevention ofintra-abdominal adhesions.

A need exists for longer term use of the combination COX-2 inhibitors(e.g., celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxibanalogue) and aspirin or active aspirin derivatives (e.g., PC-ASA orPL2200) in the following conditions: osteoarthritis, other arthritides,chronic pain, prophylaxis of chronic migraine, cancer prevention, cancertreatment, and prevention or treatment of pre-cancerous intestinal(colon or rectal) polyps, including use in the setting of familialadenomatous polyposis (PAP).

A need exists for regular periodic or short-term use of the combinationof COX-2 inhibitors (e.g., celecoxib, celecoxib analogue, PC-celecoxib,or PC-celecoxib analogue) and aspirin or active aspirin derivatives(e.g., PC-ASA or PL2200) in these conditions: dysmenorrhea, preventionof dysmenorrhea, menstrual or pen-menstrual migraine, prevention ofmenstrual or peri-menstrual migraine, prevention or treatment ofdysmenorrhea and menstrual or pen-menstrual migraine in patients withboth conditions, and prevention or treatment of migraine in patientswith recurring time windows where there is a need to be free of migrainesymptoms during the time windows. A need also exists for acute orsubacute pain.

Regardless of whether the celecoxib, celecoxib analogue, PC-celecoxib,or PC-celecoxib analogue and aspirin or active aspirin derivative aretaken concomitantly, at different times of the day, or even on alternatedays, there still exists the potential for adverse GI drug effects asseen in Lichtenberger's rodent study. This potential increases with thedosage used and longer periods of use and is more likely to derive fromlocal proximity of the GI mucosa to these drugs but may also derive fromsystemic absorption with subsequent effect on local tissues. The presentinvention provides an enteric or partially enteric coating on at leastone of the celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxibanalogue and the aspirin or active aspirin derivative for reducing thepotential adverse GI drug effects.

Enteric coatings and/or formulations have been used to reduce the GIside effects of various medications, including aspirin and conventionalNSAIDs. These coatings and/or formulations have also been proposed fortargeted drug delivery within the GI tract (for example, targetedabsorption in the colon for treatment of ulcerative colitis). Entericcoatings of aspirin have traditionally been designed to reduce gastricand/or duodenal GI symptoms or side effects, favoring absorption in thesmall intestine (or distally) with slower onset of action. Traditional(non-enteric) aspirin is absorbed in the gastric and/or duodenal areaand has a faster onset of action. The active derivative of aspirin(e.g., PC-ASA or PL2200) has an onset of action stated to be equivalentto traditional (non-enteric) aspirin and is therefore likely absorbed inthe gastric and/or duodenal area.

There is a need to further reduce GI side effects of the combination ofcelecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxib analogueand the aspirin or active aspirin derivative such as PC-ASA/PL2200 aswell as other forms of active aspirin derivatives. Embodiments of thisinvention that utilize enteric coating/formulation technology for eitherthe celecoxib, celecoxib analogue, PC-celecoxib, PC-celecoxib analogueor PC-ASA/PL2200 accomplish this conveniently with improved compliance.Examples of various enteric coatings for the COX-2 inhibitor and activeaspirin derivatives are provided below. These enteric coatings and/orformulations (either partial or complete) are designed to maximizeefficacy for the intended clinical purpose while preserving thecardiovascular benefits of low dose aspirin and minimizing GI sideeffects and/or toxicity.

Suitable enteric coatings include polymethacrylates (methacrylicacid/ethyl acrylate); cellulose ester polymers such as cellulose acetatephthalate or CAP (also known as “Aquateric”), cellulose acetatetrimellitate (CAT), hydroxylpropyl methyl cellulose phthalate, andhydroxylpropyl methyl cellulose acetate succinate (HPMC); polyvinylderivatives such as polyvinyl acetate phthalate or PVAP (also known as“Coateric” and “Sureteric”); methacrylic acid copolymers, and acryliccopolymers. A mixture of sodium alginate and aqueous ammonium salt ofshellac is another, “food grade,” enteric coating. The enteric coatingsmay be aqueous-based or solvent-based (e.g., organic solvent-based), andmay be present with or without a subcoating. The enteric coating may be,for example, time-sensitive, pH-sensitive, and/or microflora-activated,and may be present in a range of, for example, 10-50 wt % (e.g., 20 wt%, 25 wt %, 30 wt %, 35 wt %, 40 wt %) of the coated drug.

For bioavailability in the small intestine, preferably, the entericformulations should have less than 10% of drug release after 2 hours inthe acid stage, and completion of drug release in the continuationtesting in the buffer stage should take place within 45 minutes.Specific examples of suitable enteric coatings include “Eudragrit L 30D-55” which is a copolymer of methacrylic acid and ethyl acrylate thatdissolves at a pH of 5.5, and “Eudragrit L100” which dissolves at a pHabove 6 and may be preferable to the “L 30 D-55” product by reducingoverlapping release of the COX-2 inhibitor and aspirin (as long as anadequate absorption profile for the celecoxib or ASA component ismaintained). Both “Eudragrit L 30 D-55” and “Eudragrit L 100” areavailable from Evonik Industries AG, Essen, Germany.

Colonic targeting of the COX-2 inhibitor or celecoxib component mayrequire a formulation with improved bioavailability (BA). Onealternative is a strategy of colonic targeting by using, for example,microcapsules (which may include a self-emulsifying core) or polymericand/or non-polymeric nanoparticles of the COX-2 inhibitor or celecoxibcomponent. Once drug release has occurred at the ileal-colonic junctionor proximal colon, there would be improved absorption, as compared tothe present commercially available product. Alternatively colonictargeting by using an enteric coating of the present commerciallyavailable COX-2 inhibitor or celecoxib component would result inacceptable absorption and bioavailability. Examples of entericformulations include “Eudragrit S 100” and “Eudragrit FS 30 D” whichdissolve at a pH below 7.0 making these enteric coatings suitable forcolonic targeting (drugs typically released at or near the ileo-cecaljunction or proximal colon). Both “Eudragrit S 100” and Eudragrit “FS 30D” are available from Evonik Industries AG, Essen, Germany.Time-dependent, pro-drug, and microflora-activated systems are alsosuitable, as well as combinations of pH and time-dependent systems.Nanoparticles of celecoxib may also be useful for non-enteric orpartially enteric formulations.

In some embodiments, the aspirin or active aspirin derivative componentdoes not have an enteric coating. For embodiments where the aspirin oractive aspirin derivation has an enteric coating, a suitable coating isa polymer type that promotes pH-dependent release. In some embodiments,a taste masking pH-dependent solubility polymer can be used; such apolymer may be a ‘reverse enteric’ system that is insoluble in thehigher pH of the saliva but immediately dissolves in the acidic pH ofthe stomach.

Enteric coating of the aspirin or active aspirin derivative component(e.g., PC-ASA or PL2200) may be relatively challenging, though possible,as there can be problems with adherence of many enteric coatings andbreakdown due to the interface with a gelatin capsule often on theaspirin active derivative component. If the capsule of PC-ASA was HPMC,enteric coating would be relatively straightforward. Capsule-in-capsuletechnology, if used, requires the enteric coating of the inner capsuleto be compatible in terms of shelf life and maintenance of releaseprofile with the product and the carrier located in the interveningspace. Examples of such constructions include an inner enteric-coatedHPMC capsule with an outer hard gelatin capsule, an inner hard gelatincapsule with an outer enteric-coating HPMC capsule, both inner and outerHPMC capsules, or both inner and outer hard gelatin capsules. Analternative is over-encapsulation (a representative example wouldinclude use of the Caps Canada product).

A kit containing the COX-2 inhibitor and aspirin or active aspirinderivative may be very useful for the purpose of patient compliance andto remind patients not to take OTC aspirin or conventional NSAIDs whiletaking the combination. The use of the kit may contain instructions fortaking the active aspirin derivative or aspirin at a different time ofday than celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxibanalogue; or on alternate days, in order to reduce potential sideeffects of the drugs when taken concomitantly.

Various embodiments of kits include a kit (e.g., “C pack” or “Cel pack”or “Celsprin pack”) with separate dosing units where the COX-2 inhibitorsuch as celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxibanalogue (partially or fully enteric formulation or non-enteric) andaspirin or active aspirin derivative such as ASA, PC-ASA, or PL2200(partially or fully enteric formulation or non-enteric) are takenseparately, or alternatively a kit with a single dosage unit which mayinclude capsule-in capsule technology or other formulations where:either the celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxibanalogue is a non-enteric formulation and the aspirin or active aspirinderivative is a partially or fully enteric formulation in the samedosage unit; or the celecoxib, celecoxib analogue, PC-celecoxib, orPC-celecoxib analogue is a partially or fully enteric formulation andthe PC-ASA/PL2200 is a non-enteric formulation in the same dosage unit.Partially enteric formulation may be capsule-in-capsule or otherpartially enteric formulation.

Dosages of the COX-2 inhibitor and aspirin or aspirin derivative mayhave a tablet size of about 600 mg comprising about 200 mg of the activeingredients. In an example embodiment, the table may contain about 150mg of a COX-2 inhibitor and 50 mg of an aspirin or aspirin derivative.Other example embodiments may include 119 mg COX-2 inhibitor and 81 mgaspirin or aspirin derivative, or 125 mg COX-2 inhibitor and 75 mgaspirin or aspirin derivative.

Dosages of the celecoxib component would be in the range of 50-400 mgper day, most typically 200 mg per day (or 100 mg twice daily) forchronic conditions such as osteoarthritis (a formulation with increasedbioavailability may require fewer mg per day). Elderly patients may dowell on a smaller dose (for example, 100 mg per day) for similarconditions. In dysmenorrhea and acute pain studies for Celebrex, 400 mgwas given initially followed by an additional 200 mg if needed, then 200mg once every 12 hours for several days. Treatment of acute migraine, oracute migraine with dysmenorrhea, would be similar in dosing level todysmenorrhea (acute pain) dosing.

The recommended dose of celecoxib for familial adenomatous polyposis(FAP) is 400 mg twice daily. This dose could be lowered in some patients(e.g., for FAP, colon CA prevention and/or treatment; prevention ofpre-cancerous polyps) if the aspirin component is given concomitantly(celecoxib component in a range of 200-800 mg per day, for example). Forprevention of intra-abdominal adhesions, a dose of 100-400 mg per dayfor the celecoxib component is useful. Most guidelines for celecoxibstress use of the lowest effective dose for the condition being treated.

Prophylactic treatment of menstrual migraine may require treatment for5-15 days per cycle and would likely be in the range of 200-400 mg perday, and possibly down to 100 mg per day, if there are tolerabilityissues.

For the aspirin component, the dose for acute migraine or acute pain (ordysmenorrhea) can be as high as 1,200 mg but more typically it would bein a range of 300-650 mg, 75-325 mg, or in the range of 50-650 mg, whencombined with the celecoxib component. For familial adenomatouspolyposis (FAP) and similar conditions, a typical dose for the aspirincomponent would be 162-325 mg per day, or in the range of 50-500 mg perday.

Aspirin and aspirin derivative doses for prophylaxis of migraine can befound in U.S. Pub. No. 2003/0212050. Typically, the aspirin componentwould be 81, 162, or 325 mg for the PL2200 active aspirin derivative and81, 100, 162, 200, or 325 mg for the PA8140 and PA32540 active aspirinderivatives (dose range of 40-500 mg). The dose range would be similarfor chronic conditions (e.g., 40-325 mg daily, or 162-500 mg every otherday).

For prevention of intra-abdominal adhesions, a typical dose would be50-162 mg per day (range 40-325 mg per day) for the aspirin or activeaspirin derivative component.

In another embodiment, the celecoxib, celecoxib analogue, PC-celecoxib,or PC-celecoxib analogue is a partially or fully enteric formulation andgiven as a single dosage unit which may or may not be combined withnon-enteric aspirin or certain non-enteric active derivatives of aspirin(e.g., PC-ASA, PL2200, PA8140, or PA32540) taken separately or in akit). Partial enteric formulation may be capsule-in-capsule or otherpartially enteric formulation.

An embodiment exists where the ASA or PC-ASA is a partially or fullyenteric formulation and is given as a single dosage unit which may ormay not be combined with a non-enteric celecoxib, celecoxib analogue,PC-celecoxib, or PC-celecoxib analogue separately or in a kit. Partiallyenteric formulation may be capsule-in-capsule or other partially entericformulation.

An embodiment exists where the ASA or PC-ASA/PL2200 and the celecoxib,celecoxib analogue, PC-celecoxib, or PC-celecoxib analogue are eitherboth in a partially enteric formulation or both in a fully entericformulation targeted to the small intestine or colon (or both the smallintestine and colon).

An embodiment exists where the ASA or PC-ASA/PL2200 is in a partiallyenteric formulation and the celecoxib, celecoxib analogue, PC-celecoxib,or PC-celecoxib analogue is in a fully enteric formulation targeted tothe small intestine, colon, or both areas.

An embodiment exists where the celecoxib, celecoxib analogue,PC-celecoxib, or PC-celecoxib analogue is in a partially entericformulation and the ASA or PC-ASA is in a fully enteric formulationtargeted to the small intestine, colon, or both areas.

In embodiments containing a partially enteric formulation, it isexpected that some portion of the formulation will be absorbed in thegastric and/or duodenal areas of the intestine and the remainder of theformulation will be targeted to the small intestine, colon, or both thesmall intestine and colon.

An embodiment exists where the celecoxib, celecoxib analogue,PC-celecoxib, or PC-celecoxib analogue is in a rectal suppositoryformulation with or without aspirin or PC-ASA in the same formulation.If without an aspirin component, a non-enteric, enteric, or partiallyenteric formulation of aspirin or active derivative (PC-ASA, PL2200,PA8140, or PA32540) could be taken orally the same day or every otherday separately or separately from an oral/rectal dosage kit.

An embodiment exists where the aspirin or aspirin derivative is in arectal suppository formulation with or without celecoxib, celecoxibanalogue, PC-celecoxib, or PC-celecoxib analogue in the sameformulation. If without, a non-enteric, enteric, or partially entericformulation of celecoxib, celecoxib analogue, PC-celecoxib, orPC-celecoxib analogue could be taken orally the same day or every otherday separately or separately from an oral/rectal dosage kit.

In all of the above embodiments, a non-enteric formulation may contain afilm coating or other substances to improve the appearance and/or tasteand/or to decrease absorption in the mouth, pharynx or esophagus as longas the non-enteric formulation absorption primarily occurs in thegastric and/or proximal small intestinal area. The film coating or othersubstances may also enhance the bioavailability and/or improve thestability of the formulation or perform other functions.

Both the enteric and non-enteric formulations may also be a controlledrelease preparation as long as the enteric formulation is primarilyabsorbed in the small intestine and/or colon and the non-entericformulation is primarily absorbed in the gastric and/or proximal smallintestinal area. Such a controlled release formulation may utilizemedicated microspheres, nanospheres, polymer matrices, and/or othercontrolled release technology.

The controlled release and/or enteric/partially enteric embodiments mayexist in one capsule of a capsule-in-capsule technology or within anypart of the aspirin or aspirin derivative product (interior, inner wallof gelcap, middle of gelcap wall, coating exterior of gelcap with one ormultiple layers, or exist separately within the self-emulsifying drugdelivery system or tablet.

An embodiment exists where naproxen or PC-naproxen is substituted forthe celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxibanalogue above. Naproxen has a reversible anti-platelet effect.

An embodiment exists where ibuprofen or PC-ibuprofen (“Zavryl”) issubstituted for the celecoxib, celecoxib analogue, PC-celecoxib, orPC-celecoxib analogue. However, in these embodiments care must be takenso that the aspirin or PC-ASA/PL2200 is taken or absorbed prior to theibuprofen and that ibuprofen or PC-ibuprofen is not taken or absorbedfrom 8 hours before to about 30 minutes after the aspirin or aspirinderivative. Ibuprofen has a reversible anti-platelet effect that isknown to interfere with the irreversible anti-platelet effect ofaspirin.

An embodiment exists where another coxib, PC-coxib, conventional NSAIDor PC-NSAID that does not interfere with aspirin's anti-platelet effectis substituted for the celecoxib, celecoxib analogue, PC-celecoxib, orPC-celecoxib analogue above. Non-coxib examples are diclofenac,meloxicam, sulindac, ketorolac, and acetaminophen.

Thus, embodiments of the sequential administration of partitionedabsorption aspirin or active aspirin derivative and cox-2 inhibitor aredisclosed. The implementations described above and other implementationsare within the scope of the following claims. One skilled in the artwill appreciate that the present invention can be practiced withembodiments other than those disclosed. The disclosed embodiments arepresented for purposes of illustration and not limitation, and thepresent invention is limited only by the claims that follow.

What is claimed is:
 1. A method of treating or prophylactically treatinga patient for conditions known to precipitate inflammation with orwithout fever comprising giving the patient a single composite dosageunit having partitioned sequential bioabsorption, the single compositedosage unit comprising i) an aspirin or active aspirin derivative, andii) a COX-2 inhibitor for partitioned sequential absorption, at leastone of which has an enteric or partial enteric coating for onset ofaction and bioabsorption in a small intestine or colon and the other forrapid onset of action and absorption in a gastric area, or a duodenalarea, or both areas.
 2. The method of claim 1, wherein the aspirin oractive aspirin derivative comprises a) acetylsalicylic acid or any ofits active derivatives that can release salicylate in vivo, and b)pharmaceutically acceptable amounts of inert fillers and binders, andprovide anti-platelet effect.
 3. The method of claim 1, wherein theenteric or partial enteric coating comprises one or more coatingsselected from the group consisting of polymethacrylates, cellulose esterpolymers, cellulose acetate trimellitate, hydroxypropyl methyl cellulosephthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinylderivatives, methacrylic acid copolymers, acrylic copolymers, or amixture of sodium alginate and aqueous ammonium salt in shellac.
 4. Themethod of claim 1, wherein the administering of the aspirin or activeaspirin derivative and the COX-2 inhibitor is short-term.
 5. The methodof claim 1, wherein the administering of the aspirin or activederivative of aspirin and the COX-2 inhibitor is periodic.
 6. The methodof claim 1, wherein the aspirin or active derivative of aspirincomprises at least one of ASA, PC-ASA, PL2200, PA8140, and PA32540. 7.The method of claim 1, wherein the COX-2 inhibitor comprises celecoxib,celecoxib analogue, PC-celecoxib, or PC-celecoxib analogue.
 8. A methodof treating or prophylactically treating a patient comprising giving thepatient a composite single dosage unit having no outer enteric coatingand having partitioned sequential bioabsorption, the composite singledosage unit comprising a combination of a COX-2 inhibitor for onset ofaction and absorption in a gastric area, or a duodenal area or bothareas, and a non-enteric aspirin or active aspirin derivative having anenteric coating for sequential separation of bioabsorption of theaspirin or active aspirin derivative from bioabsorption of the COX-2inhibitor for onset of action and absorption in a small intestine orcolon, and for delayed distal release.
 9. The method of claim 8, whereinthe non-enteric aspirin or active aspirin derivative consists ofacetylsalicylic acid or any of its active derivatives that can releasesalicylate in vivo, and an enteric coating selected from one or morecoatings comprising polymethacrylates, cellulose ester polymers,cellulose acetate trimellitate, hydroxypropyl methyl cellulosephthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinylderivatives, methacrylic acid copolymers, acrylic copolymers, or amixture of sodium alginate and aqueous ammonium salt in shellac, andpharmaceutically acceptable amounts of inert fillers and binders. 10.The method of claim 8, wherein the aspirin or active derivative ofaspirin comprises at least one of ASA, PC-ASA, PL2200, PA8140, andPA32540.
 11. The method of claim 8, wherein the COX-2 inhibitorcomprises celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxibanalogue.
 12. The method of claim 8, wherein the administering of theaspirin or active aspirin derivative and the COX-2 inhibitor isshort-term.
 13. The method of claim 8, wherein the administering of theaspirin or active derivative of aspirin and the COX-2 inhibitor isperiodic.
 14. The method of claim 8, wherein bioabsorption of theaspirin or active derivative of aspirin occurs in the small intestine.15. The method of claim 8, wherein the coating is pH-sensitive,time-sensitive, and/or microflora-activated.
 16. A kit comprising anaspirin or active aspirin derivative and a COX-2 inhibitor forpartitioned sequential absorption, at least one of which has an entericor partial enteric coating for onset of action and bioabsorption in asmall intestine or colon and the other for rapid onset of action andabsorption in a gastric area, or a duodenal area, or both areas.
 17. Thekit of claim 16, wherein the COX-2 inhibitor has the enteric or partialenteric coating.
 18. The kit of claim 16, wherein the aspirin or activeaspirin derivative has the enteric or partial enteric coating.
 19. Thekit of claim 16, wherein the enteric or partial enteric coating is oneor more coatings comprising polymethacrylates, cellulose ester polymers,cellulose acetate trimellitate, hydroxypropyl methyl cellulosephthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinylderivatives, methacrylic acid copolymers, acrylic copolymers, or amixture of sodium alginate and aqueous ammonium salt in shellac.
 20. Thekit of claim 16, wherein the coating is aqueous-based or solvent-based.